High-Dose Salvage Intensity-Modulated Radiotherapy With or Without Androgen Deprivation After Radical Prostatectomy for Rising or Persisting Prostate-Specific Antigen: 5-Year Results

International Journal of

biology physics

www.redjournal.org

Clinical Investigation

High-Dose Adjuvant Radiotherapy After RadicalProstatectomy with or Without Androgen DeprivationTherapyPiet Ost, M.D., Ph.D.,* Cesare Cozzarini, M.D.,y Gert De Meerleer, M.D., Ph.D.,*Claudio Fiorino, Ph.D.,y Bruno De Potter, B.A.,* Alberto Briganti, M.D.,z

Evi V.T. Nagler, M.D.,x Francesco Montorsi, M.D.,z Valerie Fonteyne, M.D., Ph.D.,*and Nadia Di Muzio, M.D.y

Departments of *Radiotherapy and xNephrology, Ghent University Hospital, Belgium, and yDepartment of Radiotherapy,Hospital San Raffaele, and zDepartment of Urology, San Raffaele Hospital, Vita-Salute University, Milan, Italy

Received May 18, 2011, and in revised form Aug 12, 2011.

Summary

This retrospective studyevaluated the value of addingandrogen deprivation therapyto high-dose adjuvant radia-tion (>69Gy) for pT3 and/ormargin positive prostatecancer. Multivariate analysisshowed that the addition ofADT with a median durationof 6 months significantlyimproved both biochemicaland clinical outcome. Therewas a very low incidence oflate grade 3 GI toxicity, buta troubling 10% and risingincidence of late grade 3 GUtoxicity.

Reprint requests to: Dr. Piet Ost, M.D., Ph

therapy, Ghent University Hospital, De Pinte

Int J Radiation Oncol Biol Phys, Vol. -, No.

0360-3016/$ - see front matter � 2011 Elsevie

doi:10.1016/j.ijrobp.2011.09.007

Purpose: To retrospectively evaluate the outcome and toxicity in patients receiving high-dose(>69 Gy) adjuvant radiotherapy (HD-ART) and the impact of androgen deprivation therapy(ADT).Methods and Materials: Between 1999 and 2008, 225 node-negative patients were referred forHD-ARTwith or without ADT to two large academic institutions. Indications for HD-ARTwereextracapsular extension, seminal vesicle invasion (SVI), and/or positive surgicalmargins at radicalprostatectomy (RP). A dose of at least 69.1 Gy was prescribed to the prostate bed and seminalvesicle bed. TheADT consisted of a luteinizing hormoneereleasing hormone analog. The durationand indication ofADTwas left at the discretion of the treating physician. The effect ofHD-ARTandADT on biochemical (bRFS) and clinical (cRFS) relapse-free survival was examined throughunivariate andmultivariate analysis, with correction for known patient- and treatment-related vari-ables. Interaction terms were introduced to evaluate effect modification.Results: After a median follow-up time of 5 years, the 7-year bRFS and cRFSwere 84% and 88%,respectively. On multivariate analysis, the addition of ADTwas independently associated with animproved bRFS (hazard ratio [HR] 0.4, pZ 0.02) and cRFS (HR 0.2, pZ 0.008). Higher Gleasonscores and SVIwere associatedwith decreased bRFS and cRFS.A lymphadenectomy at the time ofRP independently improved cRFS (HR 0.09, pZ 0.009). The 7-year probability of late Grade 2e3toxicity was 29% and 5% for genitourinary (GU) and gastrointestinal (GI) symptoms, respectively.The absolute incidence of Grade 3 toxicity was <1% and 10% for GI and GU symptoms, respec-tively. The study is limited by its retrospective design and the lack of a standardized use of ADT.Conclusions: This retrospective study shows significantly improved bRFS and cRFS rates with theaddition of ADT to HD-ART, with low Grade 3 gastrointestinal toxicity and 10% Grade 3 genito-urinary toxicity. � 2011 Elsevier Inc.

Keywords: Adjuvant, Androgen deprivation, Dose, Prostate cancer, Radiotherapy

.D., Department of Radio-

laan 185, B-9000, Ghent,

Belgium. Tel: (þ32) 9-332-24-11; Fax: (þ32) 9-332-30-40; E-mail: piet.

[email protected]

Conflict of interest: none.

-, pp. 1e6, 2011

r Inc. All rights reserved.

Ost et al. International Journal of Radiation Oncology � Biology � Physics2

Introduction

Adjuvant radiotherapy (ART) after radical prostatectomy (RP)is associated with improved biochemical and clinicalprogression-free survival (bRFS and cRFS) in patients withhigh-risk pathologic features: extracapsular extension (ECE),seminal vesicle invasion (SVI), and/or positive surgical margins(PM) (1e3). In addition, an overall survival (OS) benefit infavor of ART was recently demonstrated by Thompson et al.(2). The tumor burden in the postoperative setting is micro-scopic, and therefore it is commonly presumed that lowerradiation doses are sufficient for disease control. Nevertheless,biochemical and local failure will occur in approximately 25%and 7e8% of patients, respectively, within 5 years after radio-therapy when doses of 60 to 64 Gy are used (1, 4, 5). Tworetrospective trials showed improved biochemical control rateswith moderate dose escalation (66e68 Gy) compared withlower doses (60e64 Gy) (6, 7). Only one study reported earlyresults of doses up to 74 Gy (8).

The addition of androgen deprivation therapy (ADT) toprimary radiotherapy for prostate cancer is well recognized (9).The biologic advantage of adding ADT to ART may be twofold:cytoreductive and synergistic. By contrast, one might argue thatboth effects are negligible because the tumor burden is micro-scopic in the postoperative setting. Moreover, in node-negativepatients after RP, no data are available from randomized trials,and the few retrospective series looking into the matter wereunderpowered (7, 8, 10, 11).

Therefore, we retrospectively evaluated the impact of ADT inpatients receiving high-dose (>69 Gy) ART (HD-ART) andreported on the toxicity of HD-ART.

Methods and Materials

Between 1999 and 2008, 225 patients were referred to theGhent University Hospital (GUH, n Z 110) and the HospitalSan Raffaele in Milan (HSR, n Z 115) for postoperative ARTafter RP because of SVI, ECE, and/or PM. All patients weretreated with HD-ART to the postoperative prostate bed, witha dose of at least 69.1 Gy (range, 69.1e79 Gy) and hada nundetectable level of postoperative prostate-specific antigen(PSA) (defined as PSA below 0.2 ng/mL). A modifiedextended lymph node dissection (ePLND) was carried out atRP in 80% of the patients, with a median of 10 nodesremoved (range, 1e40). In the remaining 20% of the patients,the preoperative risk of lymph node involvement was esti-mated below 15% according to the Roach formula (2/3 PSAþ [Gleason-6] � 10) (12), and they were clinically nodenegative on computed tomography and/or magnetic resonanceimaging.

Androgen deprivation therapy

At both institutes no ADTwas given before RP. ADTwas given to43% of the patients, for a median duration of 6 months (range,3e36 months). At both institutes, the decision to administer ADTand the duration was left at the discretion of each treating surgeon/radiation oncologist. Additional details on ADT can be found inTable 1.

Toxicity scoring

At HSR, toxicity was determined by physician assessment usingpatient interviews during radiotherapy and during the subsequentfollow-up examinations, with relevant data collected by retro-spective analysis of the clinical charts. At GUH, all patientscompleted a questionnaire before receiving HD-ART. Any GUand GI symptoms present before HD-ART and not worsening aftertreatment were not considered as radiotherapy-induced symptoms.Compared with the Common Terminology Criteria for AdverseEvents (CTCAE) scoring system, a more extensive questionnaireand scoring system developed in house were used (13, 14). Forthis study, the GUH toxicity charts were retrospectively rescoredusing the CTCAE v3.0 scoring system. Late toxicity was definedas an increase in GI and GU radiation-induced toxicity starting >3months after radiotherapy, or as any acute toxicity lasting longerthan 3 months. For each symptom, the maximal score was regis-tered using the CTCAE v3.0 scoring system (15).

Radiotherapy details

None of the patients received elective nodal irradiation. Patients weretreated with either intensity-modulated radiotherapy (IMRT) (n Z110) or three-dimensional conformal radiotherapy (3D-CRT) (n Z113) to the postoperative prostate bed, except for 2 patients treatedwith a two-dimensional technique. At GUH, a median dose of 74 Gy(range, 70e77Gy)was prescribed in 36 fractions,which correspondsto 74.9 Gy (range, 69.1e79.1 Gy) in 2-Gy equivalent doses(supposing an a/b ratio of 3) (16). Details about pretreatmentimaging, target volume definitions, and plan optimization have beendescribed previously (8, 13, 17). At HSR, a median dose of 72 Gy(range, 72.0e75.6 Gy) was prescribed at 1.8 Gy per fraction, whichcorresponds to 69.1 Gy (range, 69.1e72.6 Gy) in 2-Gy equivalentdoses (hypothesizing an a/b ratio of 3) (16). Further treatment detailshave been previously published (18).

Statistical analysis

Biochemical progression was defined as the first of two or moreincreasing PSA levels consecutively greater than 0.20 ng/mL.Clinical progression was defined as the occurrence of a localrelapse, lymph node, or hematogenous metastases. Both bRFSand cRFS were calculated from the last day of HD-ART to thedate of first biochemical/clinical progression. For the endpointbRFS and cRFS, death without progression was censored at timeof death. The Kaplan-Meier method was used to estimate the7-year bRFS, cRFS, and OS. Univariate (log-rank) and multi-variate time-to-event (Cox regression) analyses were used toexamine the influence of patient- and tumor-related (preopera-tive PSA, Gleason score, margin status, SVI, and ECE) andtreatment-related (ePLND, AD, and radiotherapy dose) factorsfor relapse after HD-ART. All variables were entered in the Coxregression model to adjust for possible confounding factors withthe preradiotherapy PSA level, Gleason score, and radiotherapydose as continuous variables. Interaction tests were used toevaluate the extent to which independent patient- and treatment-related variables modified the effect of ADT on outcome.Radiotherapy dose was entered using the 2-Gy equivalent dosesas described above. All tests were two-sided, with a significancelevel set at 0.05.

Table 1 Patient characteristics of the whole patient group and stratified according to ADT

Characteristics Whole group (n Z 225) HD-ART only (n Z 129) HD-ART þ ADT (n Z 96) p value

Median age (y, range) 64 (46e77) 65 (46e77) 64 (49e77) 0.27Median follow-up (mo, range) 60 (6e136) 60 (6e136) 60 (6e132) 0.75Median RT dose (Gy, range)* 69 (69e79) 71 (69e79) 73 (70e79) 0.001RT technique

2D 2 (<1%) 0 (0%) 2 (<1%) 0.0013D-CRT 113 (50%) 82 (36%) 31 (14%)IMRT 110 (49%) 47 (21%) 63 (28%)

Tumor stagepT2 50 (22%) 39 (17%) 11 (5%) 0.002pT3a 111 (49%) 61 (27%) 50 (22%)pT3b 61 (27%) 26 (12%) 35 (15%)pT4 3 (1%) 3 (1%) 0

Nodal stagepN0 179 (80%) 100 (44%) 79 (36%) 0.38Median number of removednodes (range)

10 (1e40) 12 (1e40) 9 (1e36) 0.01

pNx (all cN0) 46 (20%) 29 (13%) 17 (7%) 0.38Gleason score

<8 178 (79%) 111 (49%) 67 (30%) 0.0018e10 44 (20%) 15 (7%) 29 (13%)Unknown 3 (1%) 3 (1%)

Median PSA (ng/mL) beforesurgery (range)<10 129 (57%) 86 (38%) 43 (19%) 0.002>10 90 (40%) 41 (18%) 49 (22%)Unknown 6 (3%) 2 (<1%) 4 (3%)

Positive marginYes 162 (72%) 96 (43%) 66 (29%) 0.30No 62 (28%) 32 (14%) 30 (14%)Unknown 1 (<1%) 1 (<1%)

Extracapsular extensionYes 159 (71%) 83 (37%) 76 (34%) 0.02No 66 (29%) 46 (20%) 20 (9%)

Seminal vesicle invasionYes 63 (28%) 28 (12%) 35 (16%) 0.02No 162 (72%) 101 (45%) 61 (27%)

Median time between surgery andHD-ART (mo, range)

3 (0e15) 3.6 (0e8.4) 2.4 (0e15.3) 0.008

Androgen deprivation therapyYes 96 (43%) e eNo 129 (57%) e eDuration (mo)<6 2 (2%) e e6 63 (66%) e e7e12 11 (11%) e e13e24 9 (9%) e e>24 11 (11%) e e

Abbreviations:ADTZ androgen deprivation therapy; HD-ARTZ high-dose adjuvant radiotherapy; RTZ radiotherapy; 2DZ two-dimensional conventional

radiotherapy; 3D-CRTZ three-dimensional conformal radiotherapy; IMRTZ intensity-modulated radiotherapy; PSAZ prostate-specific antigen.

* Radiotherapy dose was entered as a continuous variable using the 2-Gy equivalent doses described in Materials and Methods.

Volume - � Number - � 2011 Androgen deprivation therapy with radiotherapy after prostatectomy 3

Results

Patient characteristics

The median follow-up time was 5 years. The patient characteris-tics for the whole patient group and stratified according to ADTcan be found in Table 1.

Clinical results

The 7-year bRFS was 84% (Fig. 1). On univariate analysis,Gleason score >8 and the presence of ECE and SVI wereassociated with decreased bRFS (Table 2). On multivariateanalysis, patients receiving ADT were less likely to havea biochemical recurrence (hazard ratio [HR] 0.4, p Z 0.02)

Fig. 1. Kaplan-Meier curve representing biochemical relapse-free survival.

Table 2 Kaplan-Meier estimates of biochemical and clinicalrelapse-free survival and univariate log-rank subgroup analysis

7-yearbiochemicalrelapse-freesurvival

7-yearclinical

relapse-freesurvival

All patients 84% 88%

Variable Univariatep

value Univariatep

value

PSA before surgery<10 ng/mL 84% 0.25 90% 0.31>10 ng/mL 81% 85%

Gleason score at RP<8 90% 0.001 96% 0.0018e10 57% 59%

LymphadenectomyYes 84% 0.96 87% 0.35No 83% 88%

MarginsPositive 86% 0.06 91% 0.11Negative 77% 78%

Extracapsular extensionPresent 80% 0.008 85% 0.03Absent 98% 100%

Seminal vesicle invasionPresent 70% 0.001 69% 0.001Absent 89% 94%

Androgen deprivation therapyYes 79% 0.77 83% 0.79No 86% 90%

Abbreviations: PSA Z prostate-specific antigen; RP Z radical

prostatectomy.

Ost et al. International Journal of Radiation Oncology � Biology � Physics4

(Table 3). Patients with a higher Gleason score (HR 2.6, p Z0.001) and SVI (HR 3.9, p Z 0.001) were at an increased riskfor biochemical relapse. We found no evidence for interactionbetween ADT and Gleason score (HR 0.6; 95% confidenceinterval [CI], 0.3e1.4; p Z 0.24) or SVI (HR 1.6; 95% CI,0.3e7.9; p Z 0.56).

A clinical relapse occurred in 15 patients (lymph nodemetastases in 7, bone metastases in 6, both in 2 patients), resultingin a 7-year cRFS of 88%. The results of the univariate analysis aredepicted in Table 2. On multivariate analysis, the addition of ADTto radiotherapy improved the cRFS (HR 0.2, p Z 0.008). Patientsundergoing lymphadenectomy at time of RP were also less likelyto experience a clinical relapse (HR 0.09, p Z 0.009). Conversely,higher Gleason score and SVI were independent risk factors fordecreased cRFS (Table 3). We found no statistically significantinteraction between ADT and lymphadenectomy (HR 3.3; 95%CI, 0.2e46.7; p Z0.37), Gleason score (HR 1.0; 95% CI,0.2e4.3, pZ 0.99) and SVI (HR 6.0; 95% CI, 0.4e86; pZ 0.19).This means that the effect of ADT on outcome was not differentwhether patients had high or low Gleason scores or whether or notthey had SVI.

During follow-up, 9 patients died (7 prostate cancer deaths),resulting in a 7-year OS of 94%.

Toxicity results

The 7-year probability of late Grade 2e3 GU toxicity was 29%(Fig. 2), with a 10% absolute incidence of Grade 3 toxicity. The7-year probability of late Grade 2e3 GI toxicity was 5% (Fig. 2),with only 1 patient with a Grade 3 event. Table 4 providesa detailed overview of crude late GU and GI incidences.

Discussion

Approximately 50% of node-negative patients with high-riskfeatures at RP remain without a PSA recurrence after 5 year(1e3). The addition of ART with doses of 60 to 64 Gy improves

the 5-year biochemical control in these patients to 70e74% (1e3).Consequently, to estimate the effectiveness of ART, the 70e74%bRFS must be corrected for patients without disease after 5 years(19). The actual effect of ART can then be given by the differencein bRFS between the radiotherapy and observation arms in therandomized trials, divided by the proportion of patients withdisease (19). As a result, only 50% of the patients in the ART armwere at true risk of relapse, and a biochemical recurrence wasavoided in only 20 to 24 of 50 patients at risk (1e3). It ishypothesized that dose escalation could improve these numbers.King and Kapp estimated a 3% gain in the bRFS per incrementalGy (19). In a retrospective series, doses of 68 to 69 Gy resulted inan absolute increase in bRFS of 12% compared with lower doses(5-year bRFS 83% vs 71%) (7). However, when only the patientsat risk for relapse are taken into account, the true benefit of thedose increase in that study is doubled to 24%. In the current series,a dose above 69 Gy resulted in a 5-year bRFS of 85%, translatinginto a 22e30% gain in biochemical control compared with therandomized trials (50 patients) (1e3) and a 4% gain comparedwith doses of 68 to 69 Gy (7). These data further support therationale for dose escalation in the postoperative setting. However,in our multivariate model, the continuous variable dose was notsignificant, pointing out that doses above 70 Gy might be situatedat the steep end of the dose escalation curve.

The above-mentioned gain with dose escalation should also beinterpreted in view of the addition of ADT. Currently, the addition

Table 4 Late gastrointestinal and genitourinary toxicityusing the Common Toxicity Criteria for Adverse Events v3.0

Symptom Grade Late toxicity: n (%)

Bloating Grade 1 5 (2%)Grade 2 2 (1%)

Diarrhea Grade 1 22 (10%)Grade 2 5 (2%)

Colitis Grade 1 29 (13%)Grade 2 4 (2%)Grade 3 1 (<1%)

Incontinence Grade 1 9 (4%)Grade 2 1 (<1%)

Proctitis Grade 1 6 (3%)Cystitis Grade 1 17 (8%)

Grade 2 15 (7%)Grade 3 10 (4%)

Frequency/urgency Grade 1 33 (15%)Grade 2 9 (4%)Grade 3 2 (1%)

Incontinence Grade 1 17 (8%)Grade 2 12 (5%)Grade 3 10 (4%)

Table 3 Multivariate Cox regression analysis

SurvivalHazard ratio(95% CI)

pvalue

Biochemical relapse-free survivalAndrogen deprivation therapy 0.4 (0.1e0.9) 0.021Seminal vesicle invasion 4.0 (1.8e8.8) 0.001Gleason score 2.6 (1.7e4.1) 0.001Lymphadenectomy 0.8 (0.2e2.6) 0.69PSA before surgery 1.0 (0.99e1.0) 0.19Positive surgical margins 0.6 (0.3e1.3) 0.17Extracapsular extension 6.9 (0.9e53.0) 0.07Radiation dose* 1.04 (0.97e1.1) 0.27

Clinical relapse-free survivalAndrogen deprivation therapy 0.1 (0.02e0.5) 0.004Seminal vesicle invasion 9.5 (2.4e37.3) 0.001Gleason score 6.2 (2.5e15.2) 0.001Lymphadenectomy 0.09 (0.01e0.6) 0.009PSA before surgery 1.02 (1.01e1.04) 0.001Positive surgical margins 0.9 (0.3e2.6) 0.79Extracapsular extension e 0.96Radiation dose* 1.1 (0.9e1.2) 0.49

Abbreviations: CI Z confidence interval; PSA Z prostate-specific

antigen.

* Radiotherapy dose was entered as a continuous variable using the

2-Gy equivalent doses described in Materials and Methods.

Volume - � Number - � 2011 Androgen deprivation therapy with radiotherapy after prostatectomy 5

of ADT to ART is not recommended in node-negative patientsbecause of the lack of sufficient prospective and retrospectiveevidence (9). In this context, our study represents the first retro-spective series addressing the role of concomitant ADT in patientstreated with HD-ART. Interestingly, the addition of ADT signifi-cantly improved cancer progression rates at multivariable analysis,

Fig. 2. Probability of Grade 2e3 genitourinary and gastroin-testinal late toxicity.

after all confounding factors were accounted for. The lack ofbenefit of ADT at univariate analysis might be due to an imbalanceof known prognostic factors (Table 1) (e.g., Gleason score, SVI,and median PSA). Therefore, the effect of ADT on patientoutcome might have been confounded by the presence of moreadverse prostate cancer variants. However, when the effects of allknown variables are accounted for in multivariate analysis, theaddition of ADT significantly improved prostate cancer outcomes(Table 3). The impact of ADT points out that the estimated 3%benefit in bRFS for every incremental Gy might actually besmaller. Our retrospective results need to be confirmed inprospective randomized studies, which are currently ongoing, suchas the European Organization for Research and Treatment ofCancer 22043-30041 and the ‘Radiotherapy and androgen depri-vation in combination after local surgery (RADICALS)’ trials.Unfortunately, none of these trials addresses the matter of doseescalation.

Moreover, we demonstrated that the combination treatment(ADT þ HD-ART) is associated with a good safety profile. Fewerthan 1% Grade 3 GI sequelae were observed, which is comparableto doses of 60 to 64 Gy delivered with conventional radiotherapy(1e3). This low incidence is due to the routine use of 3D-CRTand IMRT, allowing for better sparing of the rectum, which hasbeen previously demonstrated to reduce GI toxicity (7). However,we did observe a 29% probability of late Grade 2e3 GU toxicity(Fig. 2), with a 10% absolute incidence of Grade 3 toxicity. Thisis higher in comparison with doses of 60 to 66 Gy withconventional radiotherapy, observing a crude incidence of 16.4%Grade 2e3 GU toxicity (CTCAE scoring), with only 2.7% Grade3 toxicity (11). In a retrospective series (n Z 556) using a mediandose of 68 Gy, the 8-year risk of Grade 2 or more GU toxicity was23.9% with a 12.2% risk of Grade 3 sequelae (CTCAE scoring)(20). The observed higher Grade 3 GU toxicity with a dose of 68Gy (20) or higher compared with 60 to 66 Gy is probably causedby the need to include the bladder neck and vesicourethralanastomosis in the high-dose region. As a result, improvements in

Ost et al. International Journal of Radiation Oncology � Biology � Physics6

treatment techniques such as 3D-CRT and IMRT might notimprove GU toxicity.

Our study is mainly limited by its retrospective design. Therewas no standard indication for the selection of patients receivingADT. Moreover, the duration of ADT treatment was not stan-dardized. As far as we are aware, however, no guidelines exist onthis matter (9). The possible influence of ADT on toxicity andquality of life was not assessed. However, according to a single-arm prospective study, adding 2 years of LHRH analogs to ARTdid not result in any major persistent adverse effect on quality oflife (11). Furthermore, not all patients received ePLND, whichmight have introduced a significant nodal detection bias. It mightbe argued that a certain proportion of patients not receiving PLNDcould have been affected by undetected node-positive disease.However, all patients included had undetectable PSA after surgery,excluding disease persistence after surgery. Finally, the effect ofePLND was accounted for in multivariable models.

Despite these limitations, these results should be consideredhypothesis generating, and a randomized trial addressing doseescalation and ADT seems to be meaningful and feasible (19). Thecurrent results suggest that the potential gain in bRFS with a 10-Gy increase in dose should be balanced against the 10% incidencein Grade 3 GU toxicity.

Conclusion

This retrospective study shows significantly improved bRFS andcRFS rates with the addition of ADT to HD-ART, with low Grade3 GI and 10% Grade 3 GU toxicity.

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